This invention relates to a sustained-release vasodilator. More particularly, this invention relates to the novel vasodilator which is made to be of the sustained-release type by mixing an atoxic agent having vasodilating activity with a setting or thermoplastic resin and molding them.
The number of deaths caused by cerebrovascular diseases ranks second amongst the causes of deaths, and reached about 160 thousand persons per year in 1981. Among them intracerebral hemorrhage forms about 20% thereof, and subarachnoid hemorrhage forms about 10%. Particularly, subarachnoid hemorrhage occurs frequently in men of ages of from the forties to fifties. 72 Percent of subarachnoid hemorrhage is caused by cerebral aneurysm, and curing of it is carried out by a surgical operation. The surgical operation is, however, accompanied with late cerebral vasospasm at the frequency of from 30 to 50%. Prognosis of the disease complicated with such the cerebral vasospasm is not satisfactorily, and about half of the patients may have some deficit. Further, there are many cases in which cerebral aneurysm is found out several days after paroxysm and in which the level of consciousness is not good so that the operation is delayed after a certain waiting period because of fear as to complication of cerebrovascular vasospasm due to the operation. In such cases, patients may die frequently by re-rupture during the waiting period.
Although the cause of the late cerebrovascular vasospasm accompanied with subarachnoid hemorrhage has been said to be induced by the decomposed substance of hematid, the precise mechanism subsequent the said decomposition of it has not been made clear sufficiently. As curing methods thereof, conservative treatments were tried such as those of removing coagulated clot of subarachnoid space till the opposite side, by using the large quantity of steroid, phenoxybenzamine, or by using intentional hypertension therapy by means of dopamine jointly. However, none of these has succeeded in attaining an effective result. On the other hand, papaverine hydrochloride is known to be a strong cerebrovascular vasodilator and to increase cerebrovascular bloodflow upon dosing. It has, however, the disadvantage that its half-life is short due to its easily-decomposing property in liver and that in the case of peroral administration the decomposition occurs particularly quickly. Intravenous injection is ineffective for improving cerebral bloodflow because of causing hypertension due to expansion of total peripheria vessel. Large quantity systemic administration has the danger of A-V block formation and fear of side-effects such as nausea, anoreria, constipation, vertigo, headache and perspiration, etc. As to administration by intra-arterial injection, there is a large danger of embolization. Under such conditions, curing of late cerebrovascular vasospasm by administration of papaverine hydrochloride has not been sufficiently effective. (On the other hand, transient but clear remission of vasospasm is noticed by applying papaverine hydrochloride to the exposed vessel during an operation.) No complete remedy which has sure curing effect, and long lasting period of its effectiveness has been known hitherto as to the curing of late cerebrovascular vasospasm accompanied with subarachnoid hemorrhage. The inventor has studied about the effective remedies for late cerebrovascular vasospasm variously to conclude that the long-lasting sustained release type of vasodilator is effective for solving the problem. That is, an agent which is made to be a sustained-release type by mixing an atoxic agent having vasodilating activity with a setting or thermoplastic resin and then set-molding or molding them is found to be effective as the vasodilator for the delayed cerebrovascular diseases.
In general, methods for making agents to be the sustained-release types are divided roughly into two groups, i.e. physically gradual release and chemically gradual release methods. The latter has, however, troublesome problems in aspects relating to elucidation of its mechanism or confirmation of safety. On the contrary, the former, i.e. the gradually releasing method by physical method, is considered to be the more desirable one for this invention because of less problems. As such physical methods, there are mentioned the following two processes: (a) the process to capsulate the agent by covering it with a film-type covering material, and (b) the process to mix the agent into a high polymer material to disperse and then mold them to pellets. Pelleting is decided to be the desirable method for the remedy of late cerebrovascular vasospasm, etc. according to the invention, since the necessary period to release the agent gradually is about from 2 to 4 weeks.
As seen clear from the above-mentioned description, an object of the invention is to provide a sustained-release vasodilator, particularly the said vasodilator as a remedy for late cerebral vasospasm. Other objects will be become clear from the following description.